Mammalian development is a unidirectional process that depends on the proper establishment and maintenance of lineage-specific transcriptional programs to generate a multitude of differentiated cell types (1-3). Genome-wide analyses of gene expression, chromatin structure and associated modifications during distinct stages of development and across different somatic cell types support the notion that cell identity is maintained by stable and conserved chromatin pathways (4). However, the regulators and mechanisms responsible for preserving these cellular states remain poorly understood.
Ectopic expression of transcription factors is sufficient to override stable epigenetic programs and hence alter cell fate (5). For example, forced expression of pluripotency-related transcription factors in somatic cells yields induced pluripotent stem cells (iPSCs), which are transcriptionally, epigenomically, and functionally equivalent to embryonic stem cells (ESCs) (6). Similarly, forced expression of lineage-specific transcription factors drives conversion of heterologous cells into cardiac, neuronal, myeloid and other specialized cell types (7). Reprogramming transcription factors such as Oct4 and Sox2 are thought to act as “pioneer factors”, which bind to nucleosomal DNA and gradually remodel local chromatin structure to activate target genes (8). However, the reprogramming process is generally slow and inefficient, coinciding with multiple rounds of cell division and recruitment of additional cofactors.